Usage
Metformin + Saxagliptin is prescribed for type 2 diabetes mellitus in adults as an adjunct to diet and exercise to improve glycemic control. It is not indicated for type 1 diabetes or diabetic ketoacidosis. It has not been studied in combination with insulin. This combination therapy is considered when treatment with both saxagliptin and metformin is appropriate. This medication belongs to the pharmacological class of antidiabetic agents, specifically combining a dipeptidyl peptidase-4 (DPP-4) inhibitor (saxagliptin) and a biguanide (metformin).
Saxagliptin works by increasing incretin levels. Incretins help regulate blood sugar by increasing insulin release, especially after meals, and decreasing the amount of sugar produced by the liver. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Alternate Names
This combination is often referred to as saxagliptin/metformin.
Brand names: Kombiglyze XR, Komboglyze.
How It Works
Pharmacodynamics: Saxagliptin inhibits the DPP-4 enzyme, preventing the breakdown of incretin hormones, which in turn promotes insulin release and reduces glucagon secretion, leading to improved blood sugar control. Metformin primarily reduces hepatic glucose production and improves insulin sensitivity in peripheral tissues like muscle. It also slightly reduces intestinal glucose absorption.
Pharmacokinetics:
- Saxagliptin: Administered orally, saxagliptin reaches peak plasma concentration within 2 hours. It is primarily metabolized by the CYP3A4/5 enzymes and excreted in the urine, with a half-life of approximately 2.5 hours.
- Metformin: Absorbed from the gastrointestinal tract, metformin is not metabolized by the liver and is excreted unchanged in the urine, with a half-life of around 6.2 hours.
Mechanism of Action:
- Saxagliptin competitively and reversibly binds to DPP-4, increasing levels of active incretin hormones like GLP-1 and GIP. These hormones augment glucose-dependent insulin secretion and suppress glucagon secretion, thereby improving blood glucose control.
- Metformin’s mechanism is not fully understood, but it activates AMP-activated protein kinase (AMPK), leading to a reduction in hepatic glucose production. It also enhances peripheral glucose uptake and utilization.
Elimination: Saxagliptin is partially metabolized by CYP3A4/5 and excreted renally. Metformin is excreted renally primarily as unchanged drug.
Dosage
Standard Dosage
Adults:
The starting dose is individualized based on the patient’s current regimen and ranges from saxagliptin 2.5 mg/metformin 500 mg extended-release (XR) to saxagliptin 5 mg/metformin 2000 mg XR once daily, taken with the evening meal. The maximum daily dose is 5 mg saxagliptin and 2000 mg metformin XR. The dose should be titrated based on effectiveness and tolerability. The tablet should be swallowed whole and not crushed, cut, or chewed.
Children:
The safety and efficacy of Metformin + Saxagliptin have not been established in pediatric patients.
Special Cases:
- Elderly Patients: Caution is advised in elderly patients due to age-related decline in renal function. Renal function should be monitored closely.
- Patients with Renal Impairment: Dose adjustment is necessary based on glomerular filtration rate (GFR).
- GFR 60-89 mL/min: Maximum daily dose is 3000 mg metformin and 5 mg saxagliptin.
- GFR 45-59 mL/min: Maximum daily dose is 2000 mg metformin and 5 mg saxagliptin.
- GFR 30-44 mL/min: Maximum daily dose is 1000 mg metformin and 2.5 mg saxagliptin.
- GFR <30 mL/min: Metformin is contraindicated. Maximum daily dose is 2.5 mg saxagliptin.
- Patients with Hepatic Dysfunction: Metformin + Saxagliptin is contraindicated in patients with hepatic impairment.
- Patients with Comorbid Conditions: Heart failure, pancreatitis, or a history of these conditions require careful consideration of risks and benefits. Patients at risk for heart failure should be monitored closely.
Clinical Use Cases
Dosage recommendations for clinical use cases like intubation, surgical procedures, mechanical ventilation, and emergency situations are not specific to Metformin + Saxagliptin. Management of blood sugar during such situations requires individualized assessment and may involve temporary discontinuation of oral antidiabetic agents and initiation of insulin therapy.
Dosage Adjustments
Dosage adjustments are necessary for patients with renal impairment. For those with mild renal impairment (GFR 60-89 mL/min), no dose adjustment is recommended, though a dose reduction may be considered with declining renal function. With moderate to severe renal impairment, dosage adjustments are needed as detailed above in “Special Cases.” For patients with hepatic impairment, the combination is contraindicated. If patients are taking a strong CYP3A4/5 inhibitor (e.g., ketoconazole), the saxagliptin dose should be limited to 2.5 mg daily.
Side Effects
Common Side Effects
- Diarrhea
- Nausea
- Headache
- Upper respiratory tract infection symptoms (runny nose, stuffy nose, sore throat)
- Vomiting
Rare but Serious Side Effects
- Lactic acidosis (metformin)
- Pancreatitis (saxagliptin)
- Heart failure
- Severe hypersensitivity reactions (including angioedema, anaphylaxis)
- Bullous pemphigoid
- Severe and disabling arthralgia
Long-Term Effects
- Vitamin B12 deficiency (metformin)
Adverse Drug Reactions (ADR)
- Lactic acidosis (associated with metformin) - requires immediate medical attention
- Pancreatitis (associated with saxagliptin) - requires prompt medical evaluation
- Hypersensitivity reactions - necessitates immediate discontinuation of therapy
Contraindications
- Hypersensitivity to metformin or saxagliptin
- Severe renal disease (eGFR < 30 mL/min/1.73 m²)
- Diabetic ketoacidosis
- Hepatic impairment
- History of lactic acidosis
- Acute or chronic metabolic acidosis
Drug Interactions
- CYP3A4/5 Inhibitors: Strong inhibitors like ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin may increase saxagliptin exposure and require dosage adjustment.
- Carbonic Anhydrase Inhibitors (e.g., topiramate): May increase the risk of lactic acidosis with metformin.
- Iodinated Contrast Media: May temporarily impair renal function and increase risk of lactic acidosis with metformin. Metformin should be withheld before and after iodinated contrast media administration.
- Alcohol: May increase the risk of lactic acidosis with metformin.
Pregnancy and Breastfeeding
- Pregnancy: Limited human data suggest the use of metformin in pregnant women is not associated with an increased risk of major birth defects. Animal studies have shown some reproductive toxicity at high doses of saxagliptin. It is recommended that alternative therapies, like insulin, be utilized during pregnancy whenever possible.
- Breastfeeding: Both metformin and saxagliptin and/or its metabolites are excreted in animal milk. It is unknown if saxagliptin is excreted into human breast milk. Metformin has been detected in human breast milk at low levels. The use of saxagliptin/metformin is not recommended while breastfeeding.
Drug Profile Summary
- Mechanism of Action: Saxagliptin: DPP-4 inhibitor; Metformin: Reduces hepatic glucose production, enhances peripheral glucose uptake.
- Side Effects: Diarrhea, nausea, headache, upper respiratory infection symptoms, lactic acidosis, pancreatitis, heart failure.
- Contraindications: Severe renal disease, hepatic impairment, diabetic ketoacidosis.
- Drug Interactions: CYP3A4/5 inhibitors, carbonic anhydrase inhibitors, iodinated contrast agents, alcohol.
- Pregnancy & Breastfeeding: Alternative therapies are generally recommended.
- Dosage: Individualized based on patient’s current regimen, not to exceed 5 mg saxagliptin/2000 mg metformin XR daily.
- Monitoring Parameters: Blood glucose, HbA1c, renal function (eGFR, serum creatinine), signs and symptoms of pancreatitis and heart failure, vitamin B12 levels.
Popular Combinations
Metformin + Saxagliptin is itself a popular combination, but saxagliptin and metformin can each be used individually in combination with other antidiabetic agents such as sulfonylureas (e.g., glipizide) or insulin when glycemic control is not adequate with monotherapy or dual therapy.
Precautions
- General Precautions: Assess renal function before and during therapy. Monitor for signs and symptoms of lactic acidosis and pancreatitis.
- Specific Populations: Use with caution in the elderly. Contraindicated in hepatic and severe renal impairment. Not recommended in pregnancy or lactation.
- Lifestyle Considerations: Patients should follow a healthy diet and exercise regularly. Alcohol should be avoided or consumed in moderation due to the increased risk of lactic acidosis with metformin.
FAQs (Frequently Asked Questions)
A: The starting dose is individualized based on the patient’s current treatment and ranges from saxagliptin 2.5 mg/metformin 500 mg XR to saxagliptin 5 mg/metformin 2000 mg XR daily taken with the evening meal. The dose should be titrated based on therapeutic response and tolerability, not to exceed 5mg saxagliptin/2000mg metformin XR per day.
Q2: What are the common side effects?
A: Common side effects include diarrhea, nausea, headache, and upper respiratory tract infection symptoms.
Q3: When is this combination contraindicated?
A: Metformin + Saxagliptin is contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²), hepatic impairment, or a history of lactic acidosis. It is also contraindicated in patients with type 1 diabetes or diabetic ketoacidosis.
Q4: What are the serious side effects to watch out for?
A: Serious side effects include lactic acidosis (metformin), pancreatitis (saxagliptin), and heart failure.
Q5: How does renal impairment affect dosing?
A: Dose adjustment is necessary for renal impairment. The metformin component might need to be reduced or avoided entirely, and the saxagliptin component may also require dose reduction.
Q6: Can this combination be used during pregnancy or breastfeeding?
A: Generally, alternative therapies are recommended during pregnancy and breastfeeding. If used during pregnancy, careful monitoring is needed.
Q7: What are the key drug interactions?
A: Clinically significant drug interactions include those with strong CYP3A4/5 inhibitors (which require saxagliptin dose reduction), carbonic anhydrase inhibitors, and iodinated contrast media. Alcohol can increase the risk of lactic acidosis with metformin.
Q8: How should patients be monitored while on this medication?
A: Monitor blood glucose and HbA1c levels, renal function (eGFR and serum creatinine), as well as signs and symptoms of pancreatitis and heart failure. Vitamin B12 levels should be checked periodically due to the risk of deficiency with long-term metformin use.
Q9: What patient education is essential for this drug?
A: Patients should be educated about the signs and symptoms of lactic acidosis and pancreatitis and advised to seek immediate medical attention if they occur. They should also understand the importance of adherence to diet and exercise recommendations, as well as avoiding excessive alcohol intake. Furthermore, patients should be informed about the potential drug interactions.
